Efficacy of Cytotoxic Agents against Human Tumor Xenografts Is Markedly Enhanced By Coadministration of ZD1839 (Iressa), an Inhibitor of EGFR Tyrosine Kinase

摘要: The blockade of epidermal growth factor receptor (EGFR) function with monoclonal antibodies has major antiproliferative effects against human tumors in vivo. Similar some these same have also been observed specific inhibitors the EGFR-associated tyrosine kinase. One such inhibitor, p.o. active ZD1839 (Iressa), pronounced activity tumor xenografts. We now show that coadministration ZD1839, as anti-EGFR, will enhance efficacy cytotoxic agents vulvar (A431), lung (A549 and SK-LC-16 NSCL LX-1), prostate (PC-3 TSU-PR1) tumors. Oral (five times daily x 2) (i.p. every 3-4 days 4) were given for a period 2 weeks to mice well-established On this schedule, maximum tolerated dose (150 mg/kg) induced partial regression A431, expresses high levels EGFR, 70-80% inhibition among low but highly variable EGFR expression (A549, SKLC-16, TSU-PR1, PC-3), 50-55% LX-1 tumor, which very EGFR. was effective potentiating most combination treatment all tumors, irrespective status, reduction below its single-agent required optimum tolerance. inhibitory action platinums, cisplatin carboplatinum, single A431 vulvar, A549 lung, TSU-PR1 PC-3 increased several-fold when added, Although taxanes, paclitaxel or docetaxel, markedly inhibited LX-1, SK-LC-16, PC-3, combined complete usually seen. Against A549, doxorubicin 10-fold (>99%) ZD1839. folate analogue, edatrexate, whereas edatrexate resulted alone either regression, obtained. Combination gemcitabine neither added nor detracted from baseline efficacy, vinorelbine poorly tolerated. Overall, results suggest potentiation does not require target They significant clinical benefit variety widely used agents.